tbuckley/cabot-search huggingface dataset:
LAG3 transcriptomic expression correlates with high levels of PD-1, PD-L1, PD-L2, and CTLA-4 checkpoints and with high tumor mutational burden across cancers.
Authors: Jacob J. Adashek, Shumei Kato, Sarabjot Pabla, Mary Nesline, Jeffrey M. Conroy, Vivek Subbiah, Paul DePietro, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2022)

2561 Background: Lymphocyte Activation Gene 3 (LAG3) or CD223 is an immune checkpoint that can be found on various T cells: CD4+, CD8+, regulatory T cells (Tregs), natural killer T cells, natural killer cells, and plasmacytoid dendritic cells. The expression of LAG3 molecule acts to increase T-cell exhaustion, leading to decreased tumor killing as well as an increase in immune suppressive cytokine release. Many clinical trials of LAG3 inhibitors have had modest effects, but recent data suggests that the LAG3 antibody relatlimab together with nivolumab (anti-PD1) provided greater benefit than nivolumab alone in patients with melanoma. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, OmniSeq (https://www.omniseq.com/). Following removal of germline variants, synonymous variants, indels and SNVs with &lt; 5% VAF, TMB is reported as mutations/megabase. Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high LAG3 expression was calculated and Bonferroni corrected for multiple genes and cancer histologies with &gt; 40 samples. Results: A total of 116 (22.6%) tumors had high LAG3 (≥75) across 32 different histologies. Cancers with the highest proportion of LAG3 were neuroendocrine (47%), uterine (43%), sarcoma (33%), breast (31%), ovarian (30%), pancreatic (24%), lung (20%), stomach (16%), and colorectal (15%). There was significant association for high LAG3 with high PD-L1 (adj P &lt; 0.001), high PD-1 (adj P &lt; 0.0014), high PD-L2 (adj P &lt; 0.0014), high CTLA-4 (adj P &lt; 0.0014), TMB ≥10 mt/mb (adj P = 0.0504). There was no significant association between histologies colorectal (adj P = 0.1834), breast (adj P = NS), ovarian (adj P = NS), pancreatic (adj P = NS), or gender (adj P = 0.272). Conclusions: High LAG3 was found in almost a quarter of tumor samples and significantly associated with other immune checkpoints with FDA-approved drugs. Ongoing studies combining LAG3 inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit if individualized immunomic transcript interrogation is undertaken, rather than population-based approaches without employment of rationally combined agents matched to each patient’s cancer.
Efficacy and safety of high-intensity versus reduced-intensity induction in Philadelphia chromosome-positive all ineligible for HSCT.
Authors: Valerie Tran, Ian Michael Bouligny, Kyle Zacholski, Chad Michael Venn, Yanal Mufeed Alnimer, Thuy Ho, Keri Renee Maher
Journal: Journal of Clinical Oncology (2022)

e19031 Background: Treatment options for Philadelphia chromosome-positive (Ph+) ALL are increasing. When combined with TKIs, it is unclear if high-intensity regimens lead to a survival benefit compared to reduced-intensity regimens in patients that are not candidates for allogenic hematopoietic stem cell transplant (HSCT). In this study, we sought to examine outcomes of high-intensity and reduced-intensity induction regimens and concurrent TKI administration with respect to toxicity, response, and survival in non-transplant candidates. Methods: We retrospectively analyzed 31 patients with Ph+ B-ALL treated at our institution during January 2015 to January 2021 that were not candidates for HSCT. Baseline patient demographics were obtained, including age, performance status at diagnosis, cytogenetic and molecular profiling through NGS, doses of induction, toxicity, response, MRD analysis, and survival. The event for calculating the overall survival (OS) was the date of death and patients were otherwise censored at the date of last contact. Results: We divided the cohort of 31 patients into two sub-cohorts: a high-intensity cohort of 22 patients treated with TKIs and hyperCVAD, CALGB 10403, or ECOG 1910 and a low-intensity cohort of 9 patients treated with TKI + steroids + vincristine, TKI + steroids, or TKI alone. There was expectedly a significant difference in age between the two groups (p = .002) with more advanced age in the reduced-intensity cohort, though no difference in sex (p≥.999), ECOG score at diagnosis (p = .886), or Charlson Comorbidity Index score (p = .180). Grade 3 or higher toxicity was approaching statistical significance with more toxicity in the higher-intensity group (p = .075). With fewer deaths during induction, achievement of CR or CRi was higher in the reduced-intensity cohort (100% versus 73.7%), though was not significantly different between the groups (p = .288) and the median OS was not reached in either cohort (p = .935) after a median follow-up time of 3.29 years. Conclusions: Acknowledging the limits of a small sample size and retrospective nature of the study, there was no observed difference in survival between high-intensity and reduced-intensity induction with TKIs for patients ineligible for HSCT. Reduced-intensity inductions were associated with a trend toward less severe toxicity. These findings are suggestive that reduced-intensity induction with TKIs in Ph+ ALL may represent a reasonable option for those ineligible for HSCT. Prospective randomized controlled trials in this population are warranted.
Low-dose selenite synergizes with KRAS inhibitor as a dual apoptotic and ferroptotic agent in lung adenocarcinoma.
Authors: Lok Seng Chan, Johnson Liu, Lili Li, Qian Tao, Tony S. K. Mok
Journal: Journal of Clinical Oncology (2022)

e21039 Background: Selenium, an essential trace element, has long been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients refractory to cytostatic agents. Meanwhile, ferroptosis is a novel approach in cancer treatment by triggering cell death and reversing drug resistance. However, the role of selenite in targeted therapy of lung adenocarcinoma (LUAD) and its underlying mechanism to demethylation and ferroptosis are largely unknown. Methods: EGFR- and KRAS-mutant LUAD cells (H1975 EGFR p.L858R and p.T790M and H358 KRAS p.G12C ) were treated with selenite for 72 hours to examine its effect on DNA methylation, apoptosis and ferroptosis by western blot, C-11 BODIPY staining, methylation-specific PCR and transcriptome sequencing validated by qPCR and western blot. Cell proliferation and apoptosis of both cells treated with selenite and osimertinib in H1975 or adagrasib in H358 were assessed by MTS assay and western blot. Results: We confirmed selenite to be a dual apoptotic and ferroptotic agent in LUAD, associated with the activation of the p38-ATF4-CHOP axis in the unfolded protein response. This pathway linked ferroptosis with apoptosis by the upregulation of BH3-only proteins. Selenite also altered the DNA methylation machinery by downregulating DNMT1 and upregulation of TET1. We further found that low-dose selenite synergized with adagrasib in KRAS-mutant H358 but only yielded additive interaction at a high dose. Conclusions: Selenite is a dual apoptotic and ferroptotic agent with dose-dependent, oncogenic driver-dependent therapeutic effects in LUAD. These data suggest that low-dose selenite should be a potential drug candidate for the treatment of KRAS mutation-positive lung cancer.
Distribution of breast cancer molecular subtypes within receptor classifications: Lessons from the I-SPY2 Trial and FLEX Registry.
Authors: Jaeyoon Cha, Paige Warner, Robert Hiatt, Scarlett Lin Gomez, Laura van 't Veer, Allison Stover-Fiscalini, Alexander Borowsky, W. Fraser Fraser Symmans, Denise M. Wolf, Christina Yau, Douglas Yee, Angela DeMichele, Donald A. Berry, Laura Esserman, William M. Audeh, Shraddha Modh
Journal: Journal of Clinical Oncology (2022)

592 Background: Expression-based molecular subtypes of breast cancer (BC) predict tumor behavior and therapeutic response. Subtype distributions by age and sociodemographics can inform strategies for BC screening, treatment, and prognosis. The conventional approach, adopted by NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, uses HR and HER2 to label: “triple negative” (HR-HER2-), “HER2-enriched” (HR-HER2+), “luminal A” (HR+HER2-), and “luminal B” (HR+HER2+). However, immunohistochemical (IHC)-based receptor labels may not reflect clinically and epidemiologically relevant molecular subtypes that share the same nomenclature, e.g., luminal B. Methods: We compared IHC labels by HR/HER2 to molecular subtypes by MammaPrint (MP) and BluePrint (BP) for patients in the phase II neoadjuvant I-SPY2 TRIAL for high-risk, stage II-III BC (NCT01042379, n = 981) and in the multicenter, prospective FLEX Registry for stage I-III BC (NCT03053193, n = 5,679). Results: IHC labels were discordant with MP/BP in 52% of I-SPY2 and 43% of FLEX cases (Table 1). HR-HER2- had the highest concordance with basal-type (99% in I-SPY2, 88% in FLEX). HR+ labels had the least agreement with MP/BP: HR+HER2- tumors were molecularly luminal B and basal in 71% and 29% of I-SPY2 and 40% and 4% of FLEX cases, respectively. HR+HER2+ tumors were molecularly luminal A and HER2-type in 10% and 60% of I-SPY2 and 15% and 36% of FLEX cases, respectively. Of molecularly luminal B cases, only 14% in I-SPY2 and 7% in FLEX were HR+HER2+. Conclusions: IHC markers collected by population-based registries (SEER) enable BC surveillance. However, IHC labels cannot be used as surrogates for molecular subtypes by MP/BP, especially for luminal B tumors. Given the unmet need to improve management of luminal B BC, we anticipate the growing importance of molecular subtyping to inform treatment and epidemiological research. We propose that the BC research community work with SEER to update its IHC labels to avoid overlap with molecular subtype nomenclature and incorporate such modern classifications when available. [Table: see text]
Safety and efficacy of anti-VEGF antibodies in the treatment of advanced gastric carcinomas.
Authors: Mounica Vorla, Usman Ali Akbar, Daniya Sheikh, Shameera Shaik Masthan, Mounika Pusa, Aditya Bamboria, Saman Barham, Ammar Yaser Dab, Shaheryar Qazi, Adil Khan, Rana Usman Anwer, Oluwasegun Akinti, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e16005 Background: The prognosis of gastric cancer remains poor despite advances in diagnostic techniques, neoadjuvant chemo radiotherapy and surgery. This led to the development of Anti-Vascular Endothelial Growth Factor inhibitors (Anti-VEGF), which inhibit angiogenesis, inducing a state of dormancy in the tumors. In this review, we studied the safety and efficacy of Ramucirumab (RAM) and Bevacizumab (BVZ). Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase &amp; clinicaltrials.gov. A total of 311 articles were screened, and 4 studies were included. Results: When compared to placebo, in the two Phase III trials enrolling 1020 participants,RAM enhanced overall survival (OS) and progression-free survival (PFS). RAM treatment was associated with fewer hematological adverse effects, such as anemia. In addition, when administered in conjunction with CTx, bevacizumab (BVZ) improved OS (12.1m Vs 10.1m in one trial), but more clinical studies are needed to consolidate these findings. In both phase III studies with BVZ, anemia and neutropenia were shown to be less common, as shown in the table. Conclusions: Anti-VEGF inhibitors have shown to be effective in treating advanced or relapsed GC or GE CAs with minimal adverse effects. However, high-quality large prospective randomized clinical studies are still needed.[Table: see text]
The microbial characteristics of patients with esophageal squamous cell carcinoma after chemotherapy and after immunotherapy.
Authors: Yanjun Liu, Jing Zuo, Zhisong Fan, Liang Liu, Yudong Wang, Li Feng, Jing Han, Long Wang, Xue Zhang
Journal: Journal of Clinical Oncology (2022)

e16049 Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Previous studies have shown that chemotherapy and immunotherapy is affected by esophageal microbiome. The effect of esophageal microbiota on the efficacy of chemotherapy and immunotherapy for ESCC remain poorly understood. Methods: DNA was extracted from blood, oral mucosal, saliva, urine, fecal samples from 14 ESCC patients after chemotherapy and 18 ESCC patients after immunotherapy. Total microbial genomic DNA samples were extracted using an OMEGA Soil DNA Kit (D5625-01). The V3–V4 regions of bacterial 16S rRNA genes were amplified by PCR using the forward primer and the reverse primer and were sequenced with Illumina MiSeq platform. In order to comprehensively evaluate the α diversity of microbial communities, we used Chao1 and Observed Species indices to characterize the richness, Shannon and Simpson indices to characterize the diversity. PCoA were used to analyze differences in β diversity. Functions of 16S rRNA sequences were predicted using the PICRUSt2 and KEGG databases. Results: The α diversity in patients with ESCC after immunotherapy were higher than those in patients with ESCC after chemotherapy. There was a statistically significant difference in β diversities between ESCC patients after chemotherapy and ESCC patients after immunotherapy. In terms of the microbial functions in ESCC patients after chemotherapy and immunotherapy, the metabolic pathways accounted for the most. Conclusions: This study is conducive to exploring new mechanisms for tumor cells to evade host immune surveillance, providing new ideas and new strategies for the microecology-based therapy of ESCC.
Risk of contralateral breast and other cancers in patients with invasive lobular breast cancer.
Authors: Grace Mei Yee Choong, Samuel T. Savitz, Karthik Giridhar, Tufia C. Haddad, Kathryn Jean Ruddy, Judy Caroline Boughey, Matthew P. Goetz, Fergus Couch, Siddhartha Yadav
Journal: Journal of Clinical Oncology (2022)

555 Background: Women with early-stage breast cancer (BCa) are living longer, and survivorship issues including second primary cancers (SPCs) are therefore increasingly important. This study seeks to determine the risk of SPCs, including contralateral breast cancer (CBCa), in women with early-stage invasive lobular carcinoma (ILC). Methods: The study population consisted of women with BCa diagnosis between 2000-2018 within the NCI Surveillance, Epidemiology, and End Results (SEER v 3.2.9) registry and between 2000-2021 in the Mayo Clinic Cancer Registry. In the SEER registry, the standardized incidence ratios (SIR) for SPCs were estimated for adult women with histologically confirmed early stage (I-III) ILC compared to the development of any primary cancer in the general population. For reference, SIRs for SPCs for a similar patient population with invasive ductal carcinoma (IDC) of the breast were also estimated. For comparison of CBCa between ILC and IDC, follow up records from the Mayo Clinic Cancer Registry were evaluated among adult women who underwent lumpectomy or unilateral mastectomy for early stage ILC or IDC. A multivariable Cox proportional hazards regression was performed to compare the risk of CBCa between ILC and IDC while adjusting for the age at diagnosis, race/ethnicity and estrogen receptor status of the primary tumor. Results: An increased incidence (p&lt;0.05) of any SPCs and second BCa was noted for both ILC and IDC compared to the expected rate of primary cancer in the general population (Table). Interestingly, women with ILC were observed to have a significantly increased incidence of subsequent gastric cancer which was not seen for women with IDC. An SIR &gt;1.5 was noted for subsequent risk of sarcoma, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) for both ILC and IDC (Table). In the Mayo Clinic Cancer Registry of 2,218 women with ILC and 14,629 women with IDC meeting the inclusion criteria, the 5-year risk of CBCa was 2.6% and 1.5% (log rank statistic p-value =0.001) for ILC and IDC respectively. A significantly increased risk of CBCa was noted in women with ILC (Hazard Ratio 1.82, 95% CI 1.34-2.47, p&lt;0.001) compared to women with IDC in the multivariable analysis. Conclusions: Women with ILC may have an increased risk of SPC and second BCa compared to the risk of any primary cancer in the general population. The increased incidence of gastric cancer and the higher risk of CBCa in ILC survivors compared to women with IDC is intriguing and needs to be investigated further including evaluation of the role of germline genetic factors. [Table: see text]
BMC128: A rationally designed live bacterial consortium for the potentiation of immune checkpoint therapy in solid tumors.
Authors: Corinne Maurice-Dror, Osnat Tirosh, Sheerli Kruger Ben-Shabat, Shiri Eshar, Omri Plolonsky, Noa Davis, Elran Haber, Shiri Meshner, Ruth Perets
Journal: Journal of Clinical Oncology (2022)

TPS2685 Background: Immune-Checkpoint inhibitors (ICI) have transformed the treatment of solid tumors, specifically in cutaneous melanoma, clear cell renal cell carcinoma (ccRCC) and non-small cell lung cancer (NSCLC). Despite these advances, a significant proportion of patients do not respond to ICI and only a fraction of responding patients will experience durable responses. Recent reports have found that patients showing poor response to ICI are characterized by a reduced gut microbiome diversity, suggesting that the gut microbiome might affect immune activation by ICI. BMC128 is a live bacterial consortium of 4 bacterial strains predicted to induce anti-tumor immune function when given in conjunction with ICI. These strains were identified by analyzing data obtained from NSCLC and ccRCC patients presenting varied responses to ICI, using a proprietary computational discovery platform enabling high-resolution functional microbiome analysis. In pre-clinical studies, treatment with BMC128 potentiated the efficacy of ICI in breast cancer and melanoma mouse models, reducing tumor volume, increasing the number of responders, and demonstrating an increase in infiltrating immunocytes: CD4, CD8 and NK cells. Methods: In this phase I, first-in-human trial, patients with ccRCC, cutaneous melanoma and NSCLC-adenocarcinoma (EGFR/ALK wild-type), who previously progressed on PD1/PDL-1 inhibitors will be treated with BMC128 8*10 8 CFU BID in combination with Nivolumab at a fixed-dose of 480mg q4weeks in a 3+3 design, followed by a 9 patient expansion phase. No dose escalation is planned. The primary objective is to investigate the safety and tolerability of BMC128 in combination with Nivolumab. Enrollment is intended to start in Feb, 2022. Clinical trial information: 202122207. [Table: see text]
Oncology clinical trial termination trends: Analysis across the prior 20 years.
Authors: Laura Palmeri, Sergii Derkach, Liat Vidal-Fisher, X.Q Xue, Wael A. Harb, Keren Rachel Moss
Journal: Journal of Clinical Oncology (2022)

e13602 Background: Terminations of oncology clinical trials are an unavoidable potential outcome when novel anti-cancer therapeutics are evaluated, yet are a significant burden on cancer patients, institutions, regulators and the industry as a whole. Overall, approximately 1 in 5 trials are terminated – the four main reasons are poor enrollment (PE), business decisions, lack of efficacy, and toxicity. The objective of our study is to describe trends in trial terminations. Methods: We searched Citeline® Trialtrove database for oncology, phase 1-3, industry sponsored trials, started 1Jan2000-31Dec2019 listed as completed or terminated. Data collection was performed in Jan2022. For analysis purposes, they were grouped based on start year into four 5-year periods: I-2000-2004, II-2005-2009, III-2010-2014, IV-2015-2019. Undetermined phase, phase 4 and non-oncology trials were excluded. Parameters collected: phase, reason for termination (more than one could be listed), sponsor (academic involvement; Top20 pharma as determined by Scrip 100 annually). Results: A total of 21,125 trials met search criteria, of which 4,596 (22%) were indicated as terminated. Termination rate increased from period I to II (17% to 24%) and remained at a steady 22% in periods III, IV. When evaluating the rate of termination according to phase, over periods I-II-III-IV we observed an increase in the rate of termination of phase 1/2 trials - 10%, 17%, 19% and 20% respectively. Across other phases, the change in termination rates was similar to change in their proportional representation per period. In terms of reason for termination, PE remained a major reason overall, 1275 trials (28%) were terminated due to poor enrollment with a low rate of 13% in period I, followed by 37%, 29%, 21% in periods II, III, IV. Of the trials that were terminated due to PE, 51% had academic, and 73% had Top20 involvement. This is a higher representation that their respective involvement in trials. Conclusions: According to the results of our analysis, the proportion of oncology industry-sponsored terminated trials remained high over the last 20 years, with early phases (1, 1/2 &amp; 2) being the most affected. PE accounted for almost 1/3 of the overall terminations, with a possible trend of decrease. In terms sponsor type, there appeared to be a higher number of trials terminated due to PE with Top20, and with academic involvement, compared to their representation in the overall numbers. It is yet to be determined whether innovation in oncology early phase drug development, such as biomarker driven trials and seamless phase transitions will impact termination rates. Further analysis is ongoing focusing on early phase oncology trials.[Table: see text]